The accelerated non-enzymatic modifications of amino groups of proteins (short- and long-lived), lipids, and nucleic acids by reducing sugars, such as glucose and fructose, play a critical role in the pathogenesis of multiple diseases. These include diabetes mellitus, atherosclerosis Alzheimer's diseases, inflammatory arthritis, osteoarthritis, vascular stiffening, and cataract (Ishibashi Y, et al., 2013; Kroner Z, 2009; Reddy V P, et al., 2006).
The non-enzymatic glycation reaction is also called the Maillard reaction, characterized by a French scientist, Louis Camille Maillard; in 1912 (Reddy V P, et al., 2006). The Maillard reaction is comprised of multiple series of non-enzymatic reactions. In its initial phase, sugars react non-enzymatically with amino groups forming Schiff bases, which subsequently rearrange to form ketoamine or Amadori products. The Amadori product may undergo glycoxidation reaction in the presences of reactive oxygen species (ROS) and reactive nitrogen species (RNS) to form highly reactive dicarbonyl compounds. These include 3-deoxyglucosone, glyoxal, and methylglyoxal. These dicarbonyl compounds react relatively faster with amino groups of proteins, phospholipids, and nucleic acids, and hence result in the formation of a multitude of heterogonous end products, known as advanced glycation end products (AGEs) (Reddy V P, et al., 2002).
Advanced glycation end products (AGEs) formation is a slow process; therefore, AGEs accumulation is predominant on long-lived proteins, including collagens and lens crystallins under physiological milieu (Reddy V P, et al., 2006). This leads to the alteration of biological proteins functions by intra- and inter-molecular cross-links. In addition to this, AGEs form complexes with metal ions, such as Cu+ and Fe++, and hence further accelerate the formation of reactive oxygen and nitrogen species. It has been recognized that diabetes mellitus, which is characterized by hyperglycemia, is a pivotal source of AGEs in human body (Wu C H, et al., 2011; Reddy V P, et al., 2006). It has been stated that hyperglycemic environment increases the formation of AGEs, therefore, AGEs accumulation is several fold higher in diabetic individuals than normal individuals (Ahmed K A, et al., 2009). In addition to their endogenous formation, other sources of these heterogonous moieties in the human body are AGEs-enriched diet, and smoking (Wu C H, et al., 2011; Reddy V P, et al., 2006).
Several AGEs receptors, referred to as receptors for advanced glycation end products (RAGE), involve in signal transduction mechanisms. RAGE a remembers of cell surface immunoglobulin superfamily and are expressed by multiple cell types, including endothelial cells, smooth muscle cells, macrophages, and platelets. They perturb cellular functions, such as formation of intracellular generation of reactive oxygen species, followed by their recognition and interaction with AGEs. In diabetic patients, accumulation of AGEs ligands causes enhanced expressions of RAGE in vasculatures (Goldin A, et al., 2006). The AGE-RAGE interaction plays a pivotal role in the development of chronic complications, such as cardiovascular complications, nephropathy, neuropathy, and retinopathy (Reddy V P, et al., 2006).
Early attention was focused on aminoguanidine, an inhibitor of AGEs formation which sequesters reactive dicarbonyl compounds formed during the Maillard reaction. It also attenuates the oxidative stress, such as trapping of reactive nitrogen species and chelation of transition metal-ions. Although it involves in suppression of AGEs formation through combination of all these mechanisms, the drug was withdrawn from phase III clinical trials because of undesirable side effects (Adisakwattana S, et al., 2012; Reddy V P, et al., 2006). These involve flu-like symptoms, gastrointestinal disorders, deficiency of Vit-B6, and elevated levels of homocysteine (Adisakwattana S, et al., 2012; Gutierrez R M P, et al., 2010; Reddy V P, et al., 2006).